The present invention relates to the activation of Notch receptor signaling to decrease cancer cell proliferation.
Notch encodes a large protein with a single transmembrane domain, a large extracellular domain that has many tandem EGF-like repeats. Notch receptor is a signaling molecule that functions in cell development and differentiation. The Notch family includes several members for the receptor as well as ligand. Binding of ligand to a Notch receptor triggers the cleavage of the receptor at a site in the intracellular domain (ICD), releasing the activated form of the receptor which then migrates to the nucleus.
For men, prostate cancer is the second most fatal cancer after lung cancer. In advanced stages, prostate cancer metastasizes to the bone. Depending on the stage of the cancer, prostate cancer treatment involves one or a combination of the following therapies: surgery to remove the cancerous tissue, radiation therapy, chemotherapy, androgen deprivation (e.g., hormonal therapy) in the case of prostate cancer. The majority of patients who undergo hormone therapy progress to develop androgen-independent disease. Currently, there is no effective treatment for the 20-40% of prostate cancer patients who develop recurrent disease after surgery or radiation therapy, or for those in whom the cancer has metastasized at the time of diagnosis. Chemotherapy has its toxic side effects, especially in elderly patients. There is a need for new forms of prostate cancer therapy.
The present invention provides alternative methods of treating cancer that overcome the limitations of conventional therapeutic methods as well as offer additional advantages that will be apparent from the detailed description below.
In one embodiment, the invention concerns a method of decreasing the proliferation of prostate cancer cells by activating the Notch receptor.
In other embodiments, the invention provides for methods of detecting, diagnosing and alleviating prostate cancer by contacting biological samples suspected of prostate cancer. Detection and diagnosis of prostate cancer in the biological sample may include determining level of Notch expression, effects of Notch ligands on Notch receptor, or probing the biological sample with Notch receptor. Treatment may include contacting the biological sample with agonists to Notch 1 receptor or administration of a soluble Notch ligand.
In another embodiment, the invention provides an antibody which binds, preferably specifically, to Notch1. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.
Another embodiment of the invention concerns agonists and antagonists of Notch receptor as defined herein. In a particular embodiment, the agonist is an anti-Notch1 antibody, a soluble Notch1 ligand, or a small molecule.
In a still further embodiment, the invention concerns a method of identifying agonists to Notch receptor which comprise contacting the Notch receptor with a candidate molecule and monitoring a biological activity mediated by said Notch receptor. Preferably the Notch receptor is a native Notch receptor.
Another embodiment of the present invention is directed to the use of constitutively active Notch receptor, or an agonist thereof, for the preparation of a medicament useful in the treatment of a condition which is responsive to the constitutively active Notch receptor or an agonist thereof.